WO1998037881A1 - Method of treating or preventing septic shock by administering a mek inhibitor - Google Patents

Method of treating or preventing septic shock by administering a mek inhibitor Download PDF

Info

Publication number
WO1998037881A1
WO1998037881A1 PCT/US1997/023389 US9723389W WO9837881A1 WO 1998037881 A1 WO1998037881 A1 WO 1998037881A1 US 9723389 W US9723389 W US 9723389W WO 9837881 A1 WO9837881 A1 WO 9837881A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenylamino
methyl
iodo
benzamide
bromo
Prior art date
Application number
PCT/US1997/023389
Other languages
French (fr)
Inventor
Alexander James Bridges
Original Assignee
Warner Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Company filed Critical Warner Lambert Company
Priority to US09/355,680 priority Critical patent/US6251943B1/en
Priority to AU56103/98A priority patent/AU5610398A/en
Publication of WO1998037881A1 publication Critical patent/WO1998037881A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • the present invention relates to a method of treating or preventing septic shock in a patient by administering to the patient a compound that is a MEK inhibitor.
  • Septic shock is a serious medical condition that is caused by invasion of the circulatory system by bacteria. Septic shock is characterized by acute circulatory failure, usually with hypotension, followed by multiple organ failure and acute renal failure. The mortality rate of patients having septic shock is in the range of 25% to 90%. It is estimated that up to 500,000 people a year in both the United States and Europe develop septic shock.
  • the human immune system has many dedicated receptor systems that detect common pathogens, especially bacteria, and these receptor systems are distinct from the specific antibody and T-cell receptor systems, because they are permanently present, and are not tailored to meet a particular threat. Many of the dedicated receptor systems recognize the structural components of bacteria, such as lipopolysaccharide (LPS) lipoteichoic acid and peptidoglycan, and lead to activation of the immune system when these receptors bind structural components of bacteria.
  • LPS lipopolysaccharide
  • LPS LPS Binding Protein
  • TNF ⁇ tumor necrosis factor- ⁇
  • IL-l ⁇ Interleukin 1 ⁇
  • IL-6 Interleukin 6
  • AP-1 Three of the transcription factors important in inducing LBP production in the liver are AP-1 , C/EBP and STAT-3. All of these can be stimulated through the IL-6 signaling pathway, which is produced locally in the liver by Kuppfer cells.
  • IL-6 stimulates the MAP kinases (also called ERK1 and ERK2) through MEK, and these MAP kinases can activate the three transcription factors mentioned above by phosphorylation.
  • MEK MAP kinases
  • an inhibitor of MEK can decrease the stimulation of LBP gene transcription, and attenuate the strength of the macrophage response to LPS.
  • LPS signaling appears to activate all three of the known
  • MAP kinase pathways including the MEK/ERK cascade, and LPS stimulation of macrophages leads to rapid and major activation of ERKs.
  • ERK is believed to be one of the kinases that phosphorylates I ⁇ B, a prerequisite for the liberation of the transcription factor NF KB.
  • NF KB once liberated, enters the nucleus, and is probably the single most important transcriptional activator for production of TNF ⁇ .
  • an inhibitor of MEK or ERK activity could also decrease the stimulation of TNF- ⁇ gene transcription, leading to a greatly decreased physiological response to LPS.
  • MEK/MAP kinase pathway is important in septic shock, and is involved at several vital points in the progression of septic shock.
  • the present invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
  • the MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
  • the patient has septic shock.
  • the patient is at risk of having septic shock.
  • the invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
  • the MEK inhibitor is a compound of Formula I
  • R ⁇ is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifluoromethyl, or CN;
  • R2 is hydrogen;
  • R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or -(O or NH) m -(CH2) n -R9.
  • R-9 is hydrogen, hydroxy, COOH, or NRi oRn ;
  • n is 0-4;
  • m is 0 or 1-,
  • RjO an d Rl 1 independently are hydrogen or C ⁇ -Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from 0, S, NH, or N-Cj-Cg alkyl;
  • Z is COOR7, tetrazolyl, CONR 6 R 7 , CONHNR 10 Ri 1, or CH 2 OR 7 ;
  • R ⁇ and R7 independently are hydrogen, Cj-Cg alkyl, C2-C alkenyl,
  • C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R ⁇ and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
  • the MEK inhibitor is
  • 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid;
  • N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
  • the MEK inhibitor is a compound of Formula II
  • R ⁇ a is hydrogen, hydroxy, Cj-Cg alkyl, C] -Cg alkoxy, halo, trifluoromethyl, or CN;
  • R3 a , R4 a , and R5 a independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or
  • Rc (O or NH) rn -(CH2) n -R9a > where Rc; a is hydrogen, hydroxy, CO2H or NRjOaRl la- n is 0-4; m is 0 or 1 ; RlOa and R ⁇ ⁇ a independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-Ci-Cg alkyl;
  • R ⁇ a is hydrogen, Cj-Cg alkyl, C-Cj-Cg alkyl, aryl, aralkyl, or C3-C10 cycloalkyl;
  • R-j a is hydrogen, Cj-Cg alkyl, C2-C alkenyl, C2-Cg alkynyl,
  • C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc. a ); and wherein any of the foregoing alkyl, alkenyl. and alkynyl groups can be unsubstituted or substituted by cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy; or R a and R ⁇ a taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRi Oa ⁇ -l la' an d me pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
  • the present invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
  • the patients of the present invention have septic shock or are at risk of having septic shock.
  • Those skilled in the art are readily able to identify patients having septic shock.
  • patients who are at risk of having septic shock are also easily identifiable by those skilled in the art.
  • patients who are at risk of having septic shock generally comprise patients who have a bacterial infection.
  • the bacterial infection is typically a gram-negative bacterial infection.
  • the term "'patient” means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
  • the compounds of the present invention, which can be used to treat septic shock, are MEK inhibitors.
  • a MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled "Enzyme Assays" in United States Patent Number 5,525,625, column 6, beginning at line 35. The complete disclosure of United States Patent Number 5,525,625 is hereby inco ⁇ orated by reference.
  • An example of a MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-
  • a compound is a MEK inhibitor if a compound shows activity in the assay titled "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the United States Patent Number 5,525,625 and/or shows activity in the assay titled “In Vitro MEK Assay” at column 7, lines 4 to 27 of the above-referenced patent.
  • the MEK inhibitors of the present method can be administered to a patient as part of a pharmaceutically acceptable composition.
  • the compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
  • Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols
  • propyleneglycol, polyethyleneglycol, glycerol, and the like suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example sugars, sodium chloride, and the like.
  • Prolonged abso ⁇ tion of the injectable pharmaceutical form can be brought about by the use of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • abso ⁇ tion accelerators as for example, quaternary ammonium compounds
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubil
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and
  • the compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day.
  • a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable.
  • the specific dosage used can vary.
  • the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
  • the compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, -fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is inco ⁇ orated herein by reference.)
  • esters of the compounds of this invention examples include Cj-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary
  • the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, C1 -C3 alkyl primary amines and Cj-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood.
  • the compounds of the present method can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the compounds of the present method can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
  • aryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms.
  • typical aryl groups include phenyl, naphthyl, and fluorenyl.
  • the aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
  • Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
  • aryloxy means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.
  • Heteroaryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl.
  • the heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
  • substituted heteroaryl groups include chloropyranyl, me hylthienyl, fluoropyridyl, amino- 1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydro xyindolyl.
  • the heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
  • alkyl means straight and branched chain aliphatic groups. Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
  • alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein.
  • Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl.
  • Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, l,l-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
  • Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
  • Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2-(piperidin-l-yl)-ethyl, 3-(mo ⁇ holin-4-yl)propyl.
  • Alkenyl means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1 , 1 -dimethyl- hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl.
  • the alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoet .
  • alkynyl means a straight or branched carbon chain having at least one triple bond.
  • Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl.
  • the alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl- 5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.
  • the alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds.
  • typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
  • cycloalkyl means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.
  • the ring can optionally contain one, two, or three heteroatoms selected from O, S, or N.
  • Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, mo ⁇ holinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl.
  • the cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl,
  • Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1.
  • L is a leaving group, for example halo such as fluoro.
  • the reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base.
  • a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base.
  • the reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days.
  • the product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
  • the 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt.
  • organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide.
  • the free acids can also be reacted with an alcohol of the formula HOR7
  • Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ),
  • DCC 1,3-dicyclohexylcarbodiimide
  • PyBrOP bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate
  • PyBOP bis(triazolyloxy) tripyrrolidino phosphonium hexafluorophosphate
  • the phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added.
  • a base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.
  • the coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
  • the benzamides of the invention are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNRgR7.
  • the reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent.
  • Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene.
  • Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C.
  • the product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation.
  • the benzyl alcohols of the invention, compounds of Formula I where Z is CH2 ⁇ Rg and R ⁇ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
  • Typical reducing agents commonly employed include borane in tetrahydrofuran.
  • the reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
  • Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
  • the organic phase was dried (MgSOz j ) and then boiled over a steambath to low volume and cooled to room temperature.
  • the off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
  • the reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate.
  • the organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate.
  • the combined organic layers were allowed to evaporate to dryness in an open fume hood.
  • the residue was taken up in 2 mL of 50%o acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 ⁇ M spherical silica, pore size 1 15 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.
  • Step b Preparation of 5-chloro-2-fluoro-benzaldehvde oxime
  • Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative. This process is depicted in Scheme la.
  • L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
  • halo such as fluoro, chloro, bromo or iodo
  • an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
  • the reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide.
  • the reaction generally is carried out at a temperature of about -78°C to about 25°C, and normally is complete within about 2 hours to about 4 days.
  • the product can be isolated by removing the solvent, for example by evaporation under " reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
  • the phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNRg a OR7 a in the presence of a peptide coupling reagent.
  • Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl- isopropoxy amine, and tetrahydro-oxazine.
  • Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ),
  • phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added.
  • a base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.
  • the coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
  • An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in
  • Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3.
  • L is a leaving group such as halo
  • a base is triethylamine or diisopropylamine.
  • Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane: The organic phase was dried (MgSU4) and then concentrated over a steambath to low volume (10 mL) and cooled to room temperature.
  • the off- white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
  • This intermediate was dissolved in 25 mL of ethanolic hydrogen chloride, and the solution was allowed to stand at room temperature for 15 minutes.
  • the reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with dichloromethane ⁇ dichloromethane-methanol (166:1) afforded 0.2284 g of a light-brown viscous oil.
  • aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary evaporator to a crude solid.
  • the solid product was partitioned between diethyl ether (150 mL) and aq. HCl (330 mL, pH 0).
  • the aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12).
  • These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid.
  • the resulting suspension was extracted with ether (2 x 200 mL).
  • the combined organic extracts were dried (MgSO4), concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford
  • Examples 3 to 12 in the table below were prepared by the general procedure of Examples la and 2a.
  • EXAMPLES 13a-77a Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
  • the reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate.
  • the organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate.
  • the combined organic layers were allowed to evaporate to dryness in an open fume hood.
  • MBP myelin basic protein
  • GST-MAPK glutathione S-transferase fusion protein containing p45MEK
  • the assay solution contained 20 mM HEPES, pH 7.4,
  • GST-MEK j was incubated with 5 ⁇ g of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, so only kinase activity attributed to the added MEK remains. Incubations were 15 minutes at 30°C in a final volume of 50 ⁇ L containing 50 mM Tris (pH 7.5), 10 ⁇ M MgCl2, 2 ⁇ M EGTA, and 10 ⁇ M [ ⁇ - 3 2p]ATP.
  • GST-MEK-2E When these sites are phosphorylated, MEK activity is increased. Phosphorylation of these sites can be mimicked by mutation of the serine residues to glutamate.
  • 5 ⁇ g GST-MEK-2E was incubated with 5 ⁇ g GST-MAPK-KA for 15 minutes at 30°C in the same reaction buffer as described above. Reactions were terminated and analyzed as above.
  • the resulting supernatant was transferred to fresh tubes and incubated with 10 ⁇ L of a polyclonal antisera raised against a fragment of MAP kinase for a minimum of 1 hour at 4°C. Seventy microliters of a slurry of agarose beads coupled with protein G and protein A was added and the incubation continued for an additional 30 minutes at 4°C. The beads were pelleted by centrifugation at 13,000 x g for 5 minutes and washed three times with 1 mL RIPA buffer. Laemmli sample buffer was added to the final bead pellet. This mixture was boiled for 5 minutes then resolved on a 10%> acrylamide gel.
  • Proteins on the gel were transferred to a nitrocellulose membrane and nonspecific binding sites on the membrane blocked by incubation with 1%> ovalbumin and 1% bovine serum albumin in TBST (150 mM NaCl, 10 mM Tris (pH 7.4), and 0.05% Tween 20).
  • the membrane was then incubated with a commercially available antibody directed against phosphotyrosine. Antibody bound on the membrane was detected by incubation with 125 ⁇ _p r0le i n A, followed by autoradiography.
  • Cells were plated into multi-well plates at 10 to 20,000 cells/mL. Forty-eight hours after seeding, compounds were added to the cell growth medium and incubation was continued for 2 additional days. Cells were then removed from the wells by incubation with trypsin and enumerated with a Coulter counter.
  • Cells were seeded into 35-mm dishes at 5 to 10,000 cells/dish using growth medium containing 0.3% agar. After chilling to solidify the agar, cells were transferred to a 37°C incubator. After 7 to 10 days growth, visible colonies were manually enumerated with the aid of a dissecting microscope.

Abstract

The present invention provides a method of treating or preventing septic shock. Specifically, the present invention provides a method of treating or preventing septic shock by administering to a patient a MEK inhibitor.

Description

METHOD OF TREATING OR PREVENΗNG SEPΗC SHOCK BY ADMINISTERING A MEK INHIBITOR
FIELD OF THE INVENTION
The present invention relates to a method of treating or preventing septic shock in a patient by administering to the patient a compound that is a MEK inhibitor.
BACKGROUND OF THE INVENTION
Septic shock is a serious medical condition that is caused by invasion of the circulatory system by bacteria. Septic shock is characterized by acute circulatory failure, usually with hypotension, followed by multiple organ failure and acute renal failure. The mortality rate of patients having septic shock is in the range of 25% to 90%. It is estimated that up to 500,000 people a year in both the United States and Europe develop septic shock.
The human immune system has many dedicated receptor systems that detect common pathogens, especially bacteria, and these receptor systems are distinct from the specific antibody and T-cell receptor systems, because they are permanently present, and are not tailored to meet a particular threat. Many of the dedicated receptor systems recognize the structural components of bacteria, such as lipopolysaccharide (LPS) lipoteichoic acid and peptidoglycan, and lead to activation of the immune system when these receptors bind structural components of bacteria.
LPS, a major component of the outer cell membrane of gram-negative bacteria, appears to be a major factor in the progression of a bacterial infection to septic shock. The principal mechanism for recognition by the human immune system of LPS is by binding of the CD 14 receptor on macrophages to LPS. This binding requires LPS Binding Protein (LBP). an inducible protein made in the liver. Once macrophages have bound and recognized LPS, the macrophages produce massive amounts of inflammatory cytokines, especially tumor necrosis factor-α (TNF α), Interleukin 1 β (IL-lβ), and Interleukin 6 (IL-6).
Three of the transcription factors important in inducing LBP production in the liver are AP-1 , C/EBP and STAT-3. All of these can be stimulated through the IL-6 signaling pathway, which is produced locally in the liver by Kuppfer cells. IL-6 stimulates the MAP kinases (also called ERK1 and ERK2) through MEK, and these MAP kinases can activate the three transcription factors mentioned above by phosphorylation. Thus, an inhibitor of MEK can decrease the stimulation of LBP gene transcription, and attenuate the strength of the macrophage response to LPS. In macrophages, LPS signaling appears to activate all three of the known
MAP kinase pathways, including the MEK/ERK cascade, and LPS stimulation of macrophages leads to rapid and major activation of ERKs. ERK is believed to be one of the kinases that phosphorylates IκB, a prerequisite for the liberation of the transcription factor NF KB. NF KB, once liberated, enters the nucleus, and is probably the single most important transcriptional activator for production of TNF α. Thus, an inhibitor of MEK or ERK activity could also decrease the stimulation of TNF-α gene transcription, leading to a greatly decreased physiological response to LPS.
In cells that contain the TNF receptor, activation of that receptor leads to turning on of many pathways that lead to toxicity in the target cell, and which culminate in apoptosis (regulated self-destruction of the cell). Multiple organ failure is more likely caused by TNF-α induced toxicity than by any other single cause. Neutral sphingomyelinase has been shown to be activated by the TNF receptor, and this, in turn, activates ceramide-activated protein kinase, which then activates the MEK MAP kinase pathway in the target cells, probably adding to the overall toxic effects of TNF.
Thus, the MEK/MAP kinase pathway is important in septic shock, and is involved at several vital points in the progression of septic shock. -_>-
SUMMARY OF THE INVENTION
The present invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
In a preferred embodiment of the invention the MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
In another preferred embodiment of the invention, the patient has septic shock.
In another preferred embodiment of the invention, the patient is at risk of having septic shock.
In a more preferred embodiment the invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
In a preferred embodiment of the invention, the MEK inhibitor is a compound of Formula I
Figure imgf000005_0001
wherein:
R\ is hydrogen, hydroxy, Cj-Cg alkyl, Ci -Cg alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen;
R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or -(O or NH)m-(CH2)n-R9. where R-9 is hydrogen, hydroxy, COOH, or NRi oRn ; n is 0-4; m is 0 or 1-, RjO and Rl 1 independently are hydrogen or C}-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from 0, S, NH, or N-Cj-Cg alkyl;
Z is COOR7, tetrazolyl, CONR6R7, CONHNR10Ri 1, or CH2OR7; Rβ and R7 independently are hydrogen, Cj-Cg alkyl, C2-C alkenyl,
O
II
C2-Cg alkynyl, C-Ci -Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or
C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R^ and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof. In a more preferred embodiment, the MEK inhibitor is
[4-Chloro-2-(lH-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine; (4-iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine;
[4-nitro-2-( 1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine;
4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid;
3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid; 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-benzoic acid; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid;
5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid; 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid;
5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 H-tetrazol-5-yl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-piperidin- 1 -yl-ethyl)-benzamide;
3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin- 1 -yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-pyridin-4-yl-ethyl)-benzamide;
4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin- 4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl-propyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-moφholin- 4-yl-ethyl)-benzamide;
5 -Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide ;
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3,4-difluoro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 2-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-ylmethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1 -yl-ethyl)-benzamide;
5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 2-(4-iodo-2-methyl- phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide; 5 -Bromo-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -y 1] -propyl } -
2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- ethyl )-benzamide;
(3-Hydroxy-pyrrolidin-l-yl)-[2-(4-iodo-2-methyl-phenylamino)- 5-nitro-phenyl]; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- ethyl)-benzamide;
5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-
2-methyl- phenylamino)- benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
N- { 3 - [4-(2-Hydroxy-ethyl)-piperazin- 1 -yl]-propyl } -2-(4-iodo- 2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide;
5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-l-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-
2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-ben-zamide; 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- ethyl)-benzamide; N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5 -Fluoro-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methy l-phenyl amino)- benzamide;
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-
5 -nitro-benzamide ;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide ;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin- 1 -yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pyrrolidin-1-yl)-; 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2~morpholin-4-yl- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide ;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin-l-;
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-B_enzyloxy-5-iodo-2-(4-iodo-2-memyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
2~(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol;
[5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; or N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide. In another preferred embodiment, the MEK inhibitor is a compound of Formula II
Figure imgf000017_0001
wherein:
R\a is hydrogen, hydroxy, Cj-Cg alkyl, C] -Cg alkoxy, halo, trifluoromethyl, or CN;
R-2a is hydrogen;
R3a, R4a, and R5a independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or
(O or NH)rn-(CH2)n-R9a> where Rc;a is hydrogen, hydroxy, CO2H or NRjOaRl la- n is 0-4; m is 0 or 1 ; RlOa and R\ \a independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-Ci-Cg alkyl;
0
II
Rβa is hydrogen, Cj-Cg alkyl, C-Cj-Cg alkyl, aryl, aralkyl, or C3-C10 cycloalkyl; R-ja is hydrogen, Cj-Cg alkyl, C2-C alkenyl, C2-Cg alkynyl,
C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRc.a); and wherein any of the foregoing alkyl, alkenyl. and alkynyl groups can be unsubstituted or substituted by cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy; or R a and Rηa taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRi Oa^-l la' and me pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
In a more preferred embodiment the MEK inhibitor is
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3 -furylmethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(l-methylprop-
2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop- 2-ynyloxy)-benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)- benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop- 2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide ;
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide
5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en-4-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-
2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2-ylmethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide;
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(ethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3 -ynyloxy)-benzamide; 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide;
5--Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide;
4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-yloxy)-benzamide ; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-
2-ynyloxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3 -furylmethoxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3 -ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-
2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide;
3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( 1 -methyl- prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-(3-fluorophenyl)-prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (4,4-dimethylpent-2-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-
(cyclopentoxy)-benzamide;
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide;
3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide;
5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide ;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3 ,4-difluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; N-Cyclopropylmethoxy-3 ,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide;
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-
3 ,4, 5 -trifluoro-benzamide ;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3 ,4-difluoro-benzamide
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide;
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; N-Cyclopropylmefhoxy-3 ,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide ;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; or
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
The patients of the present invention have septic shock or are at risk of having septic shock. Those skilled in the art are readily able to identify patients having septic shock. Moreover, patients who are at risk of having septic shock are also easily identifiable by those skilled in the art. For example, patients who are at risk of having septic shock generally comprise patients who have a bacterial infection. Moreover, the bacterial infection is typically a gram-negative bacterial infection.
The term "'patient" means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs. The compounds of the present invention, which can be used to treat septic shock, are MEK inhibitors. A MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled "Enzyme Assays" in United States Patent Number 5,525,625, column 6, beginning at line 35. The complete disclosure of United States Patent Number 5,525,625 is hereby incoφorated by reference. An example of a MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-
4-oxo-4H-[l]benzopyran. Specifically, a compound is a MEK inhibitor if a compound shows activity in the assay titled "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the United States Patent Number 5,525,625 and/or shows activity in the assay titled "In Vitro MEK Assay" at column 7, lines 4 to 27 of the above-referenced patent.
The MEK inhibitors of the present method can be administered to a patient as part of a pharmaceutically acceptable composition. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray. Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absoφtion of the injectable pharmaceutical form can be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absoφtion accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and
(i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, -fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incoφorated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include Cj-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary
Cj-Cg alkyl amines and secondary Cj-Cg dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 -C3 alkyl primary amines and Cj-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incoφorated herein by reference.
In addition, the compounds of the present method can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present method can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
As used herein, the term "aryl" means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
The term "aryloxy" means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.
"Heteroaryl" means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, me hylthienyl, fluoropyridyl, amino- 1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydro xyindolyl. The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
The term "alkyl" means straight and branched chain aliphatic groups. Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, l,l-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2-(piperidin-l-yl)-ethyl, 3-(moφholin-4-yl)propyl.
"Alkenyl" means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1 , 1 -dimethyl- hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoet.henyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl. "Alkynyl" means a straight or branched carbon chain having at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl- 5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.
The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
The term "cycloalkyl" means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can optionally contain one, two, or three heteroatoms selected from O, S, or N. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, moφholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl,
2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmoφholine-l-yl. The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way. The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of
Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1.
Scheme 1
Figure imgf000033_0001
base
Figure imgf000033_0002
where L is a leaving group, for example halo such as fluoro.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base. The reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The 2-(phenylamino)-benzoic acid (e.g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR7
(where R7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ),
1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
The benzamides of the invention, Formula I where Z is CONRgR7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNRgR7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z = CONHNRI QRJ J ) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNR1 nR} 1 • The benzyl alcohols of the invention, compounds of Formula I where Z is CH2θRg and Rβ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
Figure imgf000035_0001
Typical reducing agents commonly employed include borane in tetrahydrofuran. The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
The following detailed examples illustrate specific compounds provided by this invention.
EXAMPLE 1 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid
To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethenylbenzene
(Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated.
Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSOzj) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
*H NMR (400 MHz; DMSO): δ 9.72 (s, IH), 7.97 (dd, IH, J = 7.0, 8.7 Flz), 7.70 (d, IH, J = 1.5 Hz), 7.57 (dd, IH, J = 8.4, 1.9 Hz), 7.17 (d, IH, J = 8.2 Flz), 6.61-6.53 (m, 2H), 2.18 (s, 3H);
1 C NMR (100 MHz; DMSO): δ 169.87, 167.60, 165.12, 150.17, 150.05, 139.83, 138.49, 136.07, 135.31, 135.20, 135.07, 125.60, 109.32, 105.09, 104.87, 99.72, 99.46, 89.43, 17.52;
19F NMR (376 MHz; DMSO): δ -104.00 to -104.07 (m); IR (KBr) 1670 (C = O stretch) cm" 1 ;
MS (CI) M+1 = 372. Analysis calculated for C14H11 FINO2:
C, 45.31 ; H, 2.99; N, 3.77. Found: C, 45.21 ; H, 2.77; N, 3.64.
EXAMPLES 2-30
By following the general procedure of Example 1 , the following benzoic acids and salts were prepared:
Example Compound MP °C
No.
2 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 benzoic acid
3 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 240.5-244.5 benzoic acid
4 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5-262 phenylamino)-benzoic acid Example Compound MP °C
No.
5 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic 255-260 acrd
6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 234-238 acid
7 Sodium 5-Chloro-2-(4-iodo-2-methyl- 310-320 phenylamino)-benzoate DEC
8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic 239.5-240 acid
9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic 289-293 acid
10 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl- 233-235 phenylamino)-benzoic acid
11 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic 264-267 acid
12 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic 256-258 acid
13 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro- 218.5-220 benzoic acid
14 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic 285-288 acid DEC
15 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro- 230-234 benzoic acid
16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 218-221 acid
17 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid
18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 245-255 acid DEC Example Compound MP °C
No.
19 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 218-223
20 5-F]uoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 243-46 acid
21 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic 241-245 acid
22 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)- 218-222 benzoic acid
23 4-Fluoro-2-(3-chloro-4-iodo-2-methyl- 248-252.5 phenylamino)-benzoic acid
24 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid 208-21 1
25 3-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic 232-233 acid
26 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic 179-182 acid
27 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino)benzoic acid
28 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic 209.5-21 1 acid
29 2-Chloro-6-(4-iodo-2-methyl-phenylamino)-benzoic 171-175 acid
30 2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic 251-263 acid
EXAMPLE 31 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a 1 :1 (v/v) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgS04) and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp 120-121°C;
!H NMR (400 MHz; CDC13): δ 9.1 1 (s, IH), 7.56 (d, IH, J = 1.4 Hz), 7.46-7.41
(m, 2H), 7.20 (dd, IH, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, IH), 3.86 (t, 2H, J = 5.0 Hz), 3.61 (dd, 2H, J = 10.1 , 5.5 Hz), 2.23 (s, 3H), 1.56
(broad s, IH);
IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm"1 ;
MS (C1) M+1 = 431.
Analysis calculated for CJ6H16CIIN2O2: C, 44.62; H, 3.74; N, 6.50.
Found: 44.63; H, 3.67; N, 6.30.
EXAMPLES 32-48 By following the general procedure of Example 31, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.
Example Compound MP °C
No.
32 4-Methoxy-N-(4-methoxy-phenyl)-3-nitro- 153.5-156 benzamide
33 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzamide
34 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 102.5-104.5 methyl-benzamide Example Compound MP °C
No.
35 N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 90-91 benzamide
36 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide
37 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(l H- 285-288 DEC tetrazol-5-yl)-benzamide
38 5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide
39 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138 dimethyl-benzamide
40 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 benzoylamino]-acetic acid
41 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide
42 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 132-133.4 phenylamino)-benzamide
43 N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide
44 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l -yl]- 122-124 propyl } -2-(4-iodo-2-methyl-phenylamino)- benzamide
45 N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5- 91-93 nitro-benzamide
46 N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 97-99 benzamide
47 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl- 1 18-120 phenylamino)-benzamide
48 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144 dimethyl-benzamide EXAMPLE 49 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzγl alcohol
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC. Elution with dichloromethane afforded 0.4285 g (89%>) of a white solid; mp 99-100.5°C; lH NMR (400 MHz; DMSO): δ 7.57 (d, IH, J=1.7 Hz), 7.45 (dd, I H, J=8.4,
1.9 Hz), 7.39 (s, IH), 7.29 (t, IH, J=7.5 Hz), 6.89 (d, IH, J=8.4 Hz), 6.67-6.60 (m, IH), 5.47 (t, IH, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H);
IR (KBr) 3372 (O-H stretch) cm" 1 ; MS (CI) M+1 = 358. Analysis calculated for Cj4H13F.NO:
C, 47.08; H, 3.67; N, 3.92. Found: C, 47.17; H, 3.75; N, 3.72.
EXAMPLE 50-52 The following benzyl alcohols were prepared by the general procedure of Example 49.
Example No. Compound MP °C
50 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol
51 [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]- 126.5-128.5 methanol
52 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenylj-methanol Several invention compounds of Formula I were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL of the reagent amine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrop was freshly prepared and 50 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood.
The residue was taken up in 2 mL of 50%o acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM spherical silica, pore size 1 15 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.
EXAMPLES 53-206 The following compounds of Formula I were prepared by combinatorial methodology:
Example Compound MS
No. M-H
53 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 510 phenylamino)-benzamide
54 N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide Example Compound MS
No. M-H
55 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 577 piperidin- 1 -yl-ethyl)-benzamide
56 3,4-Djfluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide
57 N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide
58 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide
59 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin- 1 -yl-ethyl)-benzamide
60 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide
61 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 414 benzamide
62 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 551 2-methyl-phenylamino)-benzamide
63 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 580 (2-moφholin-4-yl-ethyl)-benzamide
64 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin- 501 4-yl-ethyl)-benzamide
65 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 485 1 -yl-ethyl)-benzamide
66 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 493 ethyl)-benzamide
67 N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide
68 N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 460
69 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- 384 ethyl)-benzamide
70 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- 483 ethyl)-benzamide Example Compound MS
No. M-H
71 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- . 495 propyl)-benzamide
72 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 513 1 -yl-propyl)-benzamide
73 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- 480 ethyl)-benzamide
74 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyτrolidin- 1 -yl- 467 ethyl)-benzamide
75 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-moφholin- 453 4-yl-ethyl)-benzamide
76 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 557 pyridin-4-ylmethyl-benzamide
77 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 479 4-ylmethyl-benzamide
78 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino-propyl)- 425 3 ,4-difluoro-benzamide
79 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 461 benzamide
80 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide
81 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445 4-yl-ethyl)-benzamide
82 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- 400 propyl)-benzamide
83 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 437 1 -yl-ethyl)-benzamide
84 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide
85 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 450 2-yl-ethyl)-benzamide
86 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 431 4-ylmethyl-benzamide Example Compound MS
No. M-H
87 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- -444 benzamide
88 2-(4-"Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 451 1 -yl-ethyl)-benzamide
89 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 557* 2-(4-iodo-2-methyl- phenylamino)- benzamide
90 5-Fluoro-N- { 3-[4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-propyl } - 541 * 2-(4-iodo-2-methyl- phenylamino)- benzamide
91 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- 487 benzamide
92 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 601 * 2-(4-iodo-2-methyl- phenylamino)- benzamide
93 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* phenylamino)- benzamide
94 5-Chloro-2-(4-iodo-2-meιhyl-phenylamino)-N-(2-piperidin- 1 -yl- 497* ethyl)-benzamide
95 (3-Hydroxy-pyrrolidin-l-yl)-[2-(4-iodo-2-methyl-phenylamino)- 466 5-nitro-phenyl]-
96 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 484* ethyl)-benzamide
97 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 530* phenylamino)- benzamide
98 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 518* 2-methyl- phenylamino)- benzamide
99 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 562* 2-methyl- phenylamino)- benzamide
100 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 499 pyrrolidin-1-yl)-
101 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid phenethy! 501 ester
102 N- (3-[4-(2-Hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo- 568* 2-methyl-phenylamino)- benzamide Example Compound MS
No. M-H
103 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- . 455 pyrrolidin-1-yl)-
104 5-Flυx>ro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide
105 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-l-yl- 528* ethyl)-benzamide
106 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- 542 * ethyl)-benzamide
107 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- 468 * ethyl)-benzamide
108 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2 -methyl- 472* phenylamino)-benzamide
109 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 502* 2-methyl- phenylamino)- benzamide
1 10 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide
1 1 1 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516* 2-methyl-phenylamino)- benzamide
1 12 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- 482* ethyl)-benzamide
1 13 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 489* phenylamino)-benzamide
1 14 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 556* propyl)-benzamide
1 15 N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529* phenylamino)-5-nitro- benzamide
116 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- 500* ethyl)-benzamide
117 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2 -methyl- 500* phenylamino)-benzamide Example Compound MS
No. M-H
1 18 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- .514* phenylamino)-benzamide
1 19 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 512* propyl)-benzamide
120 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-l-yl- 509* ethyl)-benzamide
121 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- 544* ethyl)-benzamide
122 N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 470* phenylamino)-benzamide
123 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516* phenylamino)-benzamide
124 N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 456* benzamide
125 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- 429* benzamide
126 N-(3-Diethylamino-propyl)-5-Ωuoro-2-(4-iodo-2-methyl- 484* phenylamino)-benzamide
127 N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 511 * 5-nitro-benzamide
128 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- 544* ethyl)-benzamide
129 2-(4-Iodo-2-methyl-phenylamino)-5 -nitro-N-(3 -piperidin- 1 -yl- 523 * propyl)-benzamide
130 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- 439 pyrrolidin-1-yl)-
131 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 558* phenylamino)-benzamide
132 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- 484* ethyl )-benzamide
133 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- 496* propyl)-benzamide Example Compound MS
No. M-H
134 [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- _ 482
[4-(2-hydroxy-ethyl)-piperazin- 1 -
135 N-(3-.Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 500* 2-methyl-phenylamino)- benzamide
136 [5-Chloro-2-(4-iodo-2-melhyl-phenylamino)-benzoylamino]-acetic 443 acid
137 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin- 1 -yl- 495 * ethyl)-benzamide
138 N-(3-Dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 483* 5-nitro-benzamide
139 N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 498* phenylamino)- benzamide
140 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 490 phenethyl ester
141 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 506 phenethyl ester
142 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 536 benzyl ester
143 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-thiobenzoic acid S- 503 benzyl ester
144 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 476 benzyl ester
145 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid S- 492 benzyl ester
146 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 409 benzamide
147 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 429 benzamide
148 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 413 benzamide
149 N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide Example Compound MS
No. M-H
150 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 593* benzamide
151 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- 567 benzamide
152 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 473 benzamide
153 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 521 benzamide
154 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 440 benzamide
155 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 486 benzamide
156 5-Chloro-N-cyclopropyl-2-(4-iodo-2-meιhyl-phenylamino)- 425 benzamide
157 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 459 benzamide
158 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 409
159 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 583
160 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 538 benzyl)-benzamide
161 N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 425
162 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide
163 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide
164 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 475 benzamide
165 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- 646 benzamide
166 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide
167 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436 Example Compound MS
No. M-H
168 2-(4-Iodo-2-methyl-phenylamino)-5-nilro-N-(4-sulfamoyl-benzyl)- 565 benzamide
169 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 469
170 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 473 benzamide
171 N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 517 benzamide
172 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 519 benzamide
173 N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 502 benzamide
174 N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 559 benzamide
175 N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 517
176 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 581 benzamide
177 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- 500 benzamide
178 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 567 benzamide
179 N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 451 benzamide
180 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 467 benzamide
181 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 533 benzamide
182 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 511 benzamide
183 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 489 benzamide
184 N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 478 benzamide Example Compound MS
No. M-H
185 N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 538 benzamide
186 N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 477 benzamide
187 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 431 benzamide
188 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide
189 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 488 benzamide
190 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 477 benzamide
191 N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 523 benzamide
192 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide
193 N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 427
194 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 461 benzamide
195 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 442 benzamide
196 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 415 benzamide
197 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide
198 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 41 1 benzamide
199 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 540 benzyl)-benzamide
200 N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 438 benzamide
201 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 411 Example Compound MS No. M-H
202 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 585 203 N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 472 204 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 601 benzyl)-benzamide
205 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 522 benzamide
206 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438 M+H
EXAMPLE 207 Preparation of |"4-Chloro-2-(lH-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine
Step a: Preparation of 5-chloro-2-fluoro-benzaIdehyde
To a solution of 1 -chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF (180 mL), at -78°C, LDA (2M solution in THF, 50 mL, 0.1 mol) was added drop wise. After stirring at -78°C for 1.5 hours, DMF (8 mL) was added to the reaction mixture and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between water and Et2θ. The E.2O layer was dried
(MgSθ4) and the solvent removed in vacuum to give 14.95 g (94%>) yield of crude aldehyde:
1 H NMR (CDCI3): δ, 10.3 (s, -C(=O)H).
Step b: Preparation of 5-chloro-2-fluoro-benzaldehvde oxime
A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for
1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2CI2. The CH2CI2 layer was dried (MgS04) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution with CH2CI2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C; Analysis calculated for C7H5NOFCI:
C, 48.44;'H, 2.90; N, 8.07. Found: C, 48.55; H, 2.69, N, 7.90.
Step c: Preparation of 5-chloro-2-fluoro-benzonirile
A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCθ3 (200 mL) solution. The mixture was extracted with E.2O. The Et2U layer was dried (K2CO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.
Step d: Preparation of 5-(5-chloro-2-fluoro-phenyl)-l H-tetrazole
A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, E.2O (100 mL) and 10%> aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (-15°C) and acidified to pH 1 with cone. HCl. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (49%>) of 5-(5-chloro-2-fluoro-phenyl)-lH- tetrazole: mp partial melt at 110°C, complete melting at 124°C); H (400 Mz, CDCI3): δ 8.19-8.08 (m, IH), 7.77-7.71 (m, IH), 7.61-7.52 (m, IH);
13C (100 Mz, CDCI3): δ 159.00, 156.49, 140.88, 133.02, 132.93, 130.73, 129.23,
129.21, 129.08, 126.05, 118.96, 118.73, 1 14.50; MS (CI) M+l = 199 (100), M = 198 (6). Step e: Preparation of |"4-Chloro-2-( 1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)- amine
To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at -78°C,.LDA (2 molar solution in THF, 1 1.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of l-(tetrazol-5-yl)-2- fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous cone. NH4CI solution and extracted with CH2CI2. The organic layer was dried (MgS04) and the solvent removed giving a crude product as an oil. The oil with CH2CI2-
>CH Cl2:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208°C; H (400 Mz, DMSO): δ 9.13 (s, IH), 8.00-7.99 (s, IH), 7.69 (s, IH), 7.55-7.52 (m, IH), 7.43-7.40 (m, IH), 7.12-7.05 (m, IH), 2.24 (s, 3H); 13C (100 Mz, CDCI3): δ 141.87, 139.28, 138.88, 135.47, 133.71, 131.65, 128.15,
123.69, 121.94, 1 16.68, 87.79, 17.22;
MS (CI) M+2 = 413 (44), M+l = 412 (85), M = 41 1 (100).
Analysis calculated for C14H1 ιN5CH-0.5H2θ: C, 39.97; H, 2.87; N, 16.65. Found: C, 38.87, H, 2.77; N, 16.47.
The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207.
EXAMPLE 208 (4-iodo-2-methyl-phenyl)-r2-(lH-tetrazol-5-yl)-phenyllamine. mp 231°C (dec)
EXAMPLE 209 r4-nitro-2-(lH-tetrazol-5-yl)-('4-iodo-2-methyl-phenyl)-amine, mp 205-208°C.
The 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of
Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative. This process is depicted in Scheme la.
Scheme la
Figure imgf000056_0001
base
Figure imgf000056_0002
f ^<6a HN— O- R 7a
Figure imgf000056_0003
where L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide. The reaction generally is carried out at a temperature of about -78°C to about 25°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under" reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNRgaOR7a in the presence of a peptide coupling reagent.
Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl- isopropoxy amine, and tetrahydro-oxazine. Typical coupling reagents include 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ),
1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in
Scheme 2. Scheme 2
Figure imgf000058_0001
where L is a leaving group. The general reaction conditions for both of the steps in Scheme 2 are the same as those described above for Scheme la.
Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3.
Figure imgf000059_0001
base
Figure imgf000059_0002
where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine.
The synthesis of invention compounds of Formula II is further illustrated by the following detailed examples.
EXAMPLE la 4-Fluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino-
5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane: The organic phase was dried (MgSU4) and then concentrated over a steambath to low volume (10 mL) and cooled to room temperature. The off- white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
! H NMR (400 MHz, DMSO): δ 9.72 (s, IH), 7.97 (dd, IH, J=7.0, 8.7 Hz), 7.70 (d, IH, J=1.5 Hz), 7.57 (dd, 1H,.J=8.4, 1.9 Hz), 7.17 (d, IH, J=8.2 Hz),
6.61-6.53 (m, 2H), 2.18 (s, 3H);
13c NMR (100 MHz, DMSO): δ 169.87, 166.36 (d, JC.F=249.4 Hz), 150.11 (d, Jc.F=1 1.4 Hz), 139.83, 138.49, 136.07, 135.26 (d, JC.F=11.5 Hz), 135.07, 125.60, 109.32, 104.98 (d, JC.F=21.1 Hz), 99.54 (d, JC.F=26.0 Hz), 89.43, 17.52; 19F NMR (376 MHz, DMSO): δ -104.00 to -104.07 (m);
IR (KBr) 1670 (C=0 stretch^m"1 ; MS (CI) M+l = 372. Analysis calculated for C14H1 1 FINO2: C, 45.31 ; H, 2.99; N, 3.77. Found: C, 45.21 ; H, 2.77; N, 3.64.
(b) Preparation of 4-Fluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide
To a stirred solution of 4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.6495 g, 0.001750 mol), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.2590 g, 0.00221 1 mol), and diisopropylethylamine (0.40 mL, 0.0023 mol) in
31 mL of an equivolume tetrahydrofuran-dichloromethane solution was added 1.18 g (0.00227 mol) of solid PyBOP ([benzotriazolyloxyjtripyrrolidino phosphonium hexafluorophosphate, Advanced ChemTech) directly. The reaction mixture was stirred for 30 minutes after which time it was concentrated in vacuo. The brown oil was treated with 10% aqueous hydrochloric acid. The suspension was extracted with ether. The organic extraction was washed with 10%> sodium hydroxide followed by another 10%> hydrochloric acid wash, was dried (MgSθ4) and concentrated in vacuo to afford 1.0 g of a light-brown foam. This intermediate was dissolved in 25 mL of ethanolic hydrogen chloride, and the solution was allowed to stand at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with dichloromethane→dichloromethane-methanol (166:1) afforded 0.2284 g of a light-brown viscous oil. Scratching with pentane- hexanes and drying under high vacuum afforded 0.1541 g (23%) of an off-white foam; mp 61-75°C; H NMR (400 MHz, DMSO): δ 1 1.34 (s, IH), 9.68 (s, IH), 9.18 (s, IH), 7.65 (d, IH. J=1.5 Hz), 7.58 (dd, IH, J=8.7, 6.8 Hz), 7.52 (dd, IH, J=8.4, 1.9 Hz), 7.15 (d, IH, J=8.4 Hz), 6.74 (dd, IH, J=l 1.8, 2.4 Hz), 6.62 (ddd, IH, J=8.4, 8.4, 2.7 Hz), 2.18 (s, 3H);
13C NMR (100 MHz, DMSO): δ 165.91 , 164.36 (d, JC.F=247.1 Hz), 146.78, 139.18, 138.77, 135.43, 132.64, 130.60 (d, JC.F=1 1.5 Hz), 122.23, 1 12.52, 104.72 (d, J=22.1 Hz), 100.45 (d, JC.F=25.2 Hz), 86.77, 17.03;
19F NMR (376 MHz, DMSO): δ -107.20 to -107.27 (m); IR (KBr) 3307 (broad, O-H stretch), 1636 (C=O stretch) cm"1 ;
MS (CI) M+l = 387. Analysis calculated for C14H12FIN2O2:
C, 43.54; H, 3.13; N, 7.25. Found: C, 43.62; H, 3.24; N, 6.98.
EXAMPLE 2a
5-Bromo-3,4-difluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid
To a stirred solution comprised of l-bromo-2,3,4-trifluorobenzene (Aldrich, 99%; 5.30 g, 0.0249 mol) in 95 mL of anhydrous tetrahydrofuran cooled to -78°C was slowly added 12.5 mL of 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran ethylbenzene solution (Aldrich). The mixture was stirred for 1 hour and transferred by canula into 700 mL of a stirred saturated ethereal carbon dioxide solution cooled to -78°C. The cold bath was removed, and the reaction mixture was stirred for 18 hours at ambient temperature. Dilute (10%) aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary evaporator to a crude solid. The solid product was partitioned between diethyl ether (150 mL) and aq. HCl (330 mL, pH 0). The aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12). These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 200 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford
5.60 g (88% yield) of an off-white powder; mp 139-142.5°C;
! H NMR (400 MHz, DMSO): δ 13.97 (broad s, IH, 8.00-7.96 (m, IH);
13C NMR (100 MHz, DMSO): δ 162.96, 129.34, 118.47, 104.54 (d, JC.F=22.9 Hz); 19F NMR (376 MHz, DMSO): δ -120.20 to -120.31 (m), -131.75 to -131.86 (m),
-154.95 to -155.07 (m);
IR (KBr) 1696 (C=O stretch)cnr 1 ;
MS (CI) M+1 = 255.
Analysis calculated for C74H2iBrF3θ2: C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35.
Found: C, 33.18; H, 0.64; N, 0.01 ; Br, 30.14; F, 22.75. (b) Preparation of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino - benzoic acid
To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino- 5-iodotoluene in- 10 mL of tetrahydrofuran at -78°C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in -tetrahydrofuran/heptane/ethylbenzene
(Aldrich) solution. The resulting green suspension was stirred vigorously for 10 minutes, after which time a solution of 1.00 g (0.00392 mol) of 5-bromo- 2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was added. The cold bath was subsequently removed, and the reaction mixture stirred for 18 hours. The mixture was concentrated, and the concentrate was treated with 100 mL of dilute
(10%o) aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 150 mL), and the combined organic extractions were dried (MgSθ4) and concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to ambient temperature, and collected by filtration. The solid was rinsed with dichloromethane, and dried in the vacuum- oven (80°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C;
*H NMR (400 MHz, DMSO): δ 9.03 (s, IH), 7.99 (dd, IH, J=7.5, 1.9 Hz), 7.57 (dd, IH, J=1.5 Hz), 7.42 (dd, IH, J=8.4, 1.9 Hz), 6.70 (dd, IH, J=8.4, 6.0 Hz), 2.24 (s, 3H); 19F NMR (376 MHz, DMSO): δ -123.40 to -123.47 (m); -139.00 to -139.14 (m);
IR (KBr) 1667 (C=0 stretc^cm"1 ;
MS (CI) M+1 = 469.
Analysis calculated for Cj4H9BrF2lNO2:
C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; 1, 27.1 1. Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05.
(c) Preparation of 5-Bromo-3 ,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide
To a stirred solution comprised of 5-bromo-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzoic acid (0.51 g, 0.001 1 mol), 0-(tetrahydro-2H- pyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine
(0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofuran- dichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24°C for 10 minutes, and then was concentrated to dryness in vacuo. The concentrate was suspended in 100 JΏL of 10% aqueous hydrochloric acid. The suspension was extracted with 125 mL of diethyl ether. The ether layer was separated, washed with 75 mL of 10%> aqueous sodium hydroxide, and then with 100 mL of dilute acid. The ether solution was dried (MgS04) and concentrated in vacuo to afford
0.62 g (100%o) of an off-white foam. The foam was dissolved in ca. 15 mL of methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography. Elution with dichloromethane→dichloromethane-methanol (99: 1) afforded 0.2233 g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSθ4) and concentrated in vacuo to afford 0.200 g of a foam. This product was triturated with pentane to afford 0.1525 g of a powder that was repurified by flash silica chromatography. Elution with dichloromethane afforded 0.0783 g (15%>) of an analytically pure title compound, mp 80-90°C;
! H NMR (400 MHz, DMSO): δ 1 1.53 (s, IH), 9.38 (s, IH), 8.82 (s, IH), 7.70 (dd, IH, J=7.0, 1.9 Hz), 7.53 (s, IH), 7.37 (dd, IH, J=8.4, 1.9 Hz), 6.55 (dd, IH, J=8.2, 6.5 Hz), 2.22 (s, 3H);
19F NMR (376 MHz, DMSO): δ -126.24 to -126.29 (m), -137.71 to -137.77 (m);
IR (KBr) 3346 (broad, O-H stretch), 1651 (C=0 stretch^m"1; MS (CI) M+l = 484.
Analysis calculated for Ci4Hi()BrF2lN2θ2: C, 34.81 ; H, 2.09; N, 5.80.
Found: C, 34.53; H, 1.73; N, 5.52,
Examples 3 to 12 in the table below were prepared by the general procedure of Examples la and 2a. EXAMPLES 13a-77a Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
Rόa I
(e.g., as shown in Scheme 1) and hydroxylamines (e.g., HN-0-R7a). A general method is given below:
To a 0.8-mL autosampler vial in a metal block was added 40 μL of a 0.5 M solution of the acid in DMF and 40 μL of the hydroxylamine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrop was freshly prepared, and 50 μL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.
The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood.
The residue was taken up in 2 mL of 50%> acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 μM spherical silica, pore Size 1 15 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes.) Fractions were collected by monitoring at 214 nM. The desired fractions were evaporated using a Zymark Turbovap. The product was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield. The structure was confirmed by mass spectroscopy. EXAMPLES 3a-77a Example Compound Melting MS
No. Point (°C) (M-H+)
3a 2-(4-bFomo-2-methyl-phenylamino)-4-fluoro-N- 56-75 dec 523 hydroxy-benzamide
4a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65 dec phenylamino)-benzamide
5a 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67 phenylamino)-N-methyl-benzamide
6a 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 105-108 (terahydropyran-2-yloxy)benzamide
7a 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 64-68 methoxybenzamide
8a 4-Fluoro-N-hydroxy-2-(4-fluoro-2-methyl- 119-135 phenylamino)-benzamide
9a 4-Fluoro-N-hydroxy-2-(2-methyl phenylamino)- 101-103 benzamide
10a 4-Fluoro-2-(4-fluor-2-methyl-phenylamino)-N- 142-146 (terahydropyran-2-yloxy)benzamide
1 1a 4-Fluoro-N-hydroxy-2-(4-cluoro-2-methyl- 133.5-135 phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
12a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 107-109.5 phenylmethoxy-benzamide
13a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 399 methoxy-benzamide
14a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 417
N-methoxy-benzamide
15a 2-(4-Bromo-2-methyl-phenylamino)- 369
3 ,4-difluoro-N-methoxy-benzamide
16a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 342*
3,4-difluoro-benzamide (M-EtO)
17a 5-Bromo-N-ethoxy-3,4-difluoro-2-(4-iodo- 509
2-methyl-phenylamino)-benzamide
18a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445
N-isopropoxy-benzamide
19a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-isopropoxy-benzamide
20a 4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 465
2-methyl-phenylamino)-benzamide Example Compound Meltinβ MS No. Point (°C) (M-H+)
21 a 3,4-Difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 483 2-meth-yl-phenylamino)-benzamide
22a 2-(4-Bromo-2-methyl-phenylamino)- 435
3,4-difluoro-N-(furan-3-ylmethoxy)-benzamide
23a 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)- 561 2-(4-iodo-2-methyl-phenylamino)-benzamide
24a 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 536
2-(4-iodo-2-methyl-phenylamino)-benzamide
25 a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 423 (prop-2-ynyloxy)-benzamide
26a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 441 N-(prop-2-ynyloxy)-benzamide
27a 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 455 N-( 1 -methyl-prop-2-ynyloxy)-benzamide
28a 2-(4-Bromo-2-methyl-phenylamino)- 407
3 ,4-difluoro-N-( 1 -methyl-prop-2-ynyloxy)- benzamide
29a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455 2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) . (M-H+)
30a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 407
3-ynyloxy)-3,4-difluoro-benzamide
31a 5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533
2-(4-iodo-2-methyl-phenylamino)-benzamide
32a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 517
N-(3-phenyl-prop-2-ynyloxy)-benzamide
33a 3,4-Difluoro-2-(4-bromo-2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide
34a 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
35a 2-(4-Bromo-2-methyl-phenylamino)- 487
3,4-difluoro-N-[3-(3-fluoro-phenyl)-prop- 2-ynyloxy] -benzamide
36a 3,4-Difluoro-N-[3-(2-fluoro-phenyl)-prop- 535
2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide
37a 5-Bromo-3,4-difluoro-N-[3-(2-fluoro-phenyl)- 613 prop-2-ynyloxy]-2-(4-iodo-2-methyl- phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+)
38a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 557* N-(3-"methyl-5-phenyl-pent-2-en-4-ynyloxy)- *(M+H) benzamide
39a 2-(4-Bromo-2-methyl-phenylamino)- 510
3,4-difluoro-N-(3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide
40a N-Ethoxy-3 ,4-difluoro-2-(4-iodo-2-methyl- 431 phenylamino)-benzamide
41 a 2-(4-Bromo-2-methyl-phenylamino)-N-ethoxy- 383 3 ,4-difluoro-benzamide
42a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 propoxy-benzamide
43 a 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445 N-propoxy-benzamide
44a 2-(4-Bromo-2-methyl-phenylamino)- 397 3 ,4-difluoro-N-propoxy-benzamide
45a 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide
46a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 427 isopropoxy-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
47a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 445 N-isopropoxy-benzamide
48a 2-(4-Bromo-2-methyl-phenylamino)- 397
3,4-difluoro-N-isopropoxy-benzamide
49a 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-isopropoxy-benzamide
50a N-Cyclobutyloxy-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
51a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-benzamide
52a N-Cyclopentyloxy-4-fluoro-2-(4-iodo-2-methyl- 453 phenylamino)-benzamide
53a N-Cyclopentyloxy-3,4-difluoro-2-(4-iodo- 471
2-methyl-phenylamino)-benzamide
54a 2-(4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-difluoro-benzamide
55a N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439
2-methyl-phenylamino)-benzamide
56a N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) . (M-H+)
57a 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopτopylmethoxy-3,4-difluoro-benzamide
58a 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro- 435
2-(4-iodo-2-methyl-phenylamino) 59a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 505
(2-phenoxy-ethoxy)-benzamide
60a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 523
N-(2-phenoxy-ethoxy)-benzamide
61a 2-(4-Bromo-2-methyl-phenylamino)- 475
3,4-difluoro-N-(2-phenoxy-ethoxy)-benzamide
62a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 481
(thiophen-2-ylmethoxy)-benzamide
63a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 499
N-(thiophen-2-ylmethoxy)-benzamide
64a 2-(4-Bromo-2-methyl-phenylamino)- 451
3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide
65a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 439
(2-methyl-allyloxy)-benzamide Example Compound Melting MS
No. Point (°C) (M-H+)
66a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 457 N-(2-methyl-allyloxy)-benzamide
67a 2-(4-Bromo-2-methyl-phenylamino)- 410
3,4-difluoro-N-(2-methyl-allyloxy)-benzamide
68a N-(But-2-enyloxy)-4-fluoro-2-(4-iodo-2-methyl- 439 phenylamino)-benzamide
69a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide
70a 2-(4-Bromo-2-methyl-ρhenylamino)-N-(but- 410
2-enyloxy)-3 ,4-difluoro-benzamide
71a 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 441
N-(prop-2-ynyloxy)-benzamide
72a N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455
2-methyl-phenylamino)-benzamide
73a 2-(4-Bromo-2-methyl-phenylamino)-N- 449
(4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide
74a N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457
2-methyl-phenylamino)-benzamide Example Compound Melting MS
No. Point (°C) . (M-H+)
75a 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3.4-difluoro-benzamide
76a N-(3-tert.-butyl-propyn-2-yl)oxy-4-fluoro- 479 2-(4-iodo-2-methyl-phenylamino)-benzamide
77a 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 577* phenylmethoxy-benzamide *CI
Enzyme Assays
Cascade assay for inhibitors of the MAP kinase pathway
Incoφoration of 32p into myelin basic protein (MBP) was assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase
(GST-MAPK) and a glutathione S-transferase fusion protein containing p45MEK (GST-MEK). The assay solution contained 20 mM HEPES, pH 7.4,
10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50 μM [γ-32P]ATP, 10 μg
GST-MEK, 0.5 μg GST-MAPK and 40 μg MBP in a final volume of 100 μL. Reactions were stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. 2p retained on the filter mat was determined using a 1205 Betaplate. Compounds were assessed at 10 μM for ability to inhibit incoφoration of 32p.
To ascertain whether compounds were inhibiting GST-MEK or GST MAPK, two additional protocols were employed. In the first protocol, compounds were added to tubes containing GST-MEK, followed by addition of GST-MAPK,
MBP and [γ-32p]ATP. In the second protocol, compounds were added to tubes containing both GST-MEK and GST-MAPK, followed by MBP and [γ-32P]ATP. Compounds that showed activity in both protocols were scored as MAPK inhibitors, while compounds showing activity in only the first protocol were scored as MEK inhibitors.
In vitro MAP kinase assay Inhibitory activity was also confinned in direct assays. For MAP kinase,
1 μg GST-MAPK was incubated with 40 μg MBP for 15 minutes at 30°C in a final volume of 50 μL containing 50 mM Tris (pH 7.5), 10 μM MgCl2, 2 μM
EGTA, and 10 μM [γ-32p]ATP. The reaction was stopped by addition of Laemmli SDS sample buffer and phosphorylated MBP resolved by electrophoresis on a 10% polyacrylamide gel. Radioactivity incoφorated into MBP was determined by autoradiography, and subsequently by excision of the bands followed by scintillation counting.
In vitro MEK assay
For evaluation of direct MEK activity, 10 μg GST-MEK j was incubated with 5 μg of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, so only kinase activity attributed to the added MEK remains. Incubations were 15 minutes at 30°C in a final volume of 50 μL containing 50 mM Tris (pH 7.5), 10 μM MgCl2, 2 μM EGTA, and 10 μM [γ-32p]ATP. The reaction was stopped by addition of Laemmli SDS sample buffer and phosphorylated GST-MAPK-KA was resolved by electrophoresis on a 10%> polyacrylamide gel. Radioactivity incoφorated into GST-MAPK-KA was determined by autoradiography, and subsequently by excision of the bands followed by scintillation counting. Additionally, an artificially activated MEK was utilized that contained serine to glutamate mutations at positions 218 and
222 (GST-MEK-2E). When these sites are phosphorylated, MEK activity is increased. Phosphorylation of these sites can be mimicked by mutation of the serine residues to glutamate. For this assay, 5 μg GST-MEK-2E was incubated with 5 μg GST-MAPK-KA for 15 minutes at 30°C in the same reaction buffer as described above. Reactions were terminated and analyzed as above.
Whole cell MAP kjnase assay
To determine if compounds were able to block activation of MAP kinase in whole cells, the following protocol was used: Cells were plated in multi-well plates and grown to confluence. Cells were then serum-deprived overnight. Cells were exposed to the desired concentrations of compound or vehicle (DMSO) for 30 minutes, followed by addition of a growth factor, for example, PDGF (100 ng/mL). After a 5-minute treatment with the growth factor, cells were washed with PBS, then lysed in a buffer consisting of 70 mM NaCl, 10 mM HEPES
(pH 7.4), 50 mM glycerol phosphate, and 1% Triton X-100. Lysates were clarified by centrifugation at 13,000 x g for 10 minutes. Five micrograms of the resulting supernatants were incubated with 10 μg microtubule associated protein-2 (Map2) for 15 minutes at 30°C in a final volume of 25 μL containing 50 mM Tris (pH 7.4), 10 mM MgCl , 2 mM EGTA and 30 μM [γ-32P]ATP. Reactions were terminated by addition of Laemmli sample buffer. Phosphorylated Map2 was resolved on 7.5%> acrylamide gels and incoφorated radioactivity determined by autoradiography and subsequent excision of the bands followed by scintillation counting.
Immunoprecipitation and antiphosphotyrosine immunoblots
To determine the state of tyrosine phosphorylation of cellular MAP kinase, cells were lysed, endogenous MAP kinase was immunoprecipitated with a specific antibody, and the resulting immunoprecipitate analyzed for the presence of phosphotyrosine as follows: confluent cells were serum-deprived overnight and treated with compounds and growth factors as described above. Cells were then scraped and pelleted at 13,000 x g for 2 minutes. The resulting cell pellet was resuspended and dissolved in 100 μL of 1%> SDS containing 1 mM NaVO4-
Following alternate boiling and vortexing to denature cellular protein, 900 μL RIPA buffer (50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% deoxycholate, and 10 mM EDTA) was added. To this mixture was added 60 μL agarose beads coupled with rabbit immunoglobulin G and 60 μL Pansorbin cells in order to clear the lysate of nonspecific binding proteins. This mixture was incubated at 4°C for 15 minutes then centrifuged at 13,000 x g for 10 minutes. The resulting supernatant was transferred to fresh tubes and incubated with 10 μL of a polyclonal antisera raised against a fragment of MAP kinase for a minimum of 1 hour at 4°C. Seventy microliters of a slurry of agarose beads coupled with protein G and protein A was added and the incubation continued for an additional 30 minutes at 4°C. The beads were pelleted by centrifugation at 13,000 x g for 5 minutes and washed three times with 1 mL RIPA buffer. Laemmli sample buffer was added to the final bead pellet. This mixture was boiled for 5 minutes then resolved on a 10%> acrylamide gel. Proteins on the gel were transferred to a nitrocellulose membrane and nonspecific binding sites on the membrane blocked by incubation with 1%> ovalbumin and 1% bovine serum albumin in TBST (150 mM NaCl, 10 mM Tris (pH 7.4), and 0.05% Tween 20). The membrane was then incubated with a commercially available antibody directed against phosphotyrosine. Antibody bound on the membrane was detected by incubation with 125τ_pr0lein A, followed by autoradiography.
Cell Growth Assays
H-Thymidine incoφoration
Cells were plated in multi-well plates and grown to near confluence. The media was then removed and replaced with growth media containing 1% bovine serum albumin. After 24-hour serum starvation, compounds and specific growth factors were added and incubations continued for an additional 24 hours. During the final 2 hours, 3H-thymidine was added to the medium. To teπninate the incubations, the medium was removed and cell layers washed twice with ice-cold phosphate-buffered saline. After the final wash, ice-cold 5%> trichloroacetic acid was added and the cells incubated for 15 minutes at room temperature. The trichloroacetic acid solution was then removed and the cell layer washed three times with distilled water. After the final wash, the cell layer was solubilized by addition of 2% sodium dodecylsulfate. Radioactivity in this solution was determined by scintillation counting.
In 3T3-L1- adipocyte cells, in which the inhibition blocks MAPK activation by insulin with an IC50 of 3 μM, the compound had no effect on the insulin stimulated uptake of radiolabeled 2-deoxyglucose, or on the insulin-stimulated synthesis of either lipid or glycogen at 10 μM concentration. This demonstrates that the inhibitor shows selectivity between the mitogenic and metabolic effects of insulin, and demonstrates that the inhibitor will show less toxicity than an inhibitor which does not show this suφrising selectivity.
Monolayer growth
Cells were plated into multi-well plates at 10 to 20,000 cells/mL. Forty-eight hours after seeding, compounds were added to the cell growth medium and incubation was continued for 2 additional days. Cells were then removed from the wells by incubation with trypsin and enumerated with a Coulter counter.
Growth in soft-agar
Cells were seeded into 35-mm dishes at 5 to 10,000 cells/dish using growth medium containing 0.3% agar. After chilling to solidify the agar, cells were transferred to a 37°C incubator. After 7 to 10 days growth, visible colonies were manually enumerated with the aid of a dissecting microscope.
Order of addition experiments established that the invention compounds are inhibiting MEK and not MAP kinase. Experiments looking at the phosphorylation of a kinase defective mutant of MAP kinase as substrate (so that there can be no autophosphorylation of the MAP kinase to complicate inteφretation) confirms that the inhibitor inhibits MEK with an IC50 essentially identical to that produced in the cascade assay.
Kinetic analysis demonstrates that the invention compounds are not competitive with ATP. Thus, they do not bind at the ATP binding site of the enzyme, which is probably the explanation as to why these compounds do not show the nonspecific kinase inhibitory activity typical of most kinase inhibitors, which do bind at the ATP binding site and which are ATP competitive.
The in vitro and in vivo biological activity of several representative compounds of Formula I and II in the foregoing assays is presented in Tables 1 and 2.
TABLE 1 Compound of In Vitro In Vivo
Example No. % Inhibition IC50 μM % Inhibition IC50 μM
4 0.005 i 3 0.0111 10 2 0.014 3 1 0.019
32 0.028
53 0.047 0.54
33 0.052
5 0.066
6 0.071
7 0.072
8 0.086
9 0.097
34 0.098
10 0.101 55 0.114
35 0.121
11 0.128
36 0.129
12 0.135
54 0.158
13 0.178 TABLE 1
Compound of In Vitro In Vivo
Example No. % Inhibition IC50 μM % Inhibition IC50 μM
14 0.179
15 0.194
31 0.226
37 0.237
92 0.253
184 0.278
16 0.323
96 0.374
57 0.399
38 0.412
49 0.418 3
17 0.434
18 0.446
91 0.449
39 0.497
93 0.521
19 0.524 50% at 30 μM
186 0.555
20 0.557
187 0.561
21 0.569
90 0.604
89 0.614
40 0.651 30% at 30 μM
188 0.771
189 0.859
41 0.872
51 0.887 TABLE 1
Compound of In Vitro In Vivo
Example No. % Inhibition IC50 μM % Inhibition IC50 μM
42 0.920
190 0.921
43 >1.000
95 1.001
208 1.215
191 1.355
209 1.372
44 1.481
22 1.581 30% at 30 μM
23 1.588
45 1.755
192 1.797
46 1.814
47 1.91 1
24 1.944
48 1.945
100 1.994
91 2.071
27 2.269
52 2.346
25 2.363
26 2.609 50% at 30 μM
193 2.902
28 3.670
194 4.952
29 5.331
195 12.831
30 105 10 TABLE 2
Compound of In vitro In vivo
Example No. IC so (μM) IC so (μM)
- - la 0.007 0.05
2a 0.003 0.03
3a 0.072 3
4a 0.023 1
5a 0.566 -30
6a 0.345 -30
7a 0.221 <30
8a 7.13 3
9a 0.409 1
1 1a 0.334 0.5
12a 0.826
13a 0.243
14a 0.061 >2
17a 0.014
20a 0.042 0.17
21a 0.014
22a 0.137
23a 0.016
24a 0.021 0.12
25a 0.102
27a 0.026
28a 0.728
29a 0.076 0.73
30a 0.971
31a 0.045
32a 0.017
33a 0.374
34a 0.113 1.5
36a 0.056 0.07 TABLE 2
Compound of In vitro In vivo
Example No. IC so (μM) IC so (μM)
, 40a 0.028 0.125
41a 0.236
42a 0.087
43a 0.040 0.100
44a 0.475
45a 0.126
47a 0.087 0.13
49a 0.085
50a 0.043 0.22
53a 0.140
55a 0.047
56a 0.014
57a 0.181
58a 0.018 0.014
59a 0.259
62a 0.086
63a 0.019
64a 0.279
65a 0.057
66a 0.016 0.13
68a 0.119
69a 0.016
70a 0.224
71a 0.015 0.39
74a 0.035
77a 0.28

Claims

What is claimed is:
1. A method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of a compound that is a MEK inhibitor.
2. The method of Claim 1 wherein the compound is 2-(2-amino- 3-methoxyphenyl)-4-oxo-4H-[l]benzopyran.
3. The method of Claim 1 wherein the patient has septic shock.
4. The method of Claim 1 wherein the patient is at risk of having septic shock.
A method of treating or preventing septic shock, the method comprising administering to a patient having septic shock or at risk of having septic shock a therapeutically acceptable amount of 2-(2-amino-3- methoxyphenyl)-4-oxo-4H- [ 1 jbenzopyran.
The method of Claim 1 wherein the MEK inhibitor is a compound of Formula I
Figure imgf000084_0001
wherein:
Ri is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN; R2 is hydrogen; R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or -(0 or NH)m-(CH2)n-R9, where R9 is hydrogen, hydroxy, COOH, or NR10Rn ; n is 0-4; m is 0 or 1 ; RjO and R\ \ independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from 0, S, NH, or N-Cj-Cg alkyl;
Z is COOR7, tetrazolyl, CONRgR7, CONHNRJ QRJ or CH2OR7;
Rg and R7 independently are hydrogen, Cj-Cg alkyl, C2-C alkenyl,
O II
C2-C alkynyl, C-Cj-Cg alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or
C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S,
NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
7. The method of Claim 6 wherein the MEK inhibitor is
[4-Chloro-2-(lH-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine; (4-iodo-2-methyl-phenyl)-[2-(lH-tetrazol-5-yl)-phenyl]amine; [4-nitro-2-(lH-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine; 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid; 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid; 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid; 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-benzoic acid; 5 -Chloro-N-(2 -hydroxy ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 H-tetrazol-5-yl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide; 5-Bjomo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide;
5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide ; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-piperidin- 1 -yl-ethyl)-benzamide;
3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
3 ,4-Difluoro-N-(3 -hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin- 1 -yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-pyridin-4-yl-ethyl)-benzamide ; 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-moφholin-4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin- 4-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- l-yl-ethyl)-benzamide;
3,4-Difluoro-2-(4-iodό-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl- propyl)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl-propyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl- ethyl)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-moφholin- 4-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- pyridin-4-ylmethyl-benzamide ; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl)-3,4-difluoro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- 1 -yl-ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen- 2-yl-ethyl)-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-ylmethyl-benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide;
2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1 -yl-ethyl)-benzamide; 5 -Chloro-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-propyl } -
2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-propyl}- 2-(4-iodo-2-methyl- phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide;
5-Bromo-N- { 3 - [4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -propyl } - 2-(4-iodo-2-methyl- phenylamino)- benzamide; 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide; (3 -Hydroxy-pyrrolidin- 1 -yl)- [2-(4-iodo-2-methyl-phenylamino)-
5-nitro-phenyl];
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide;
5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide;
N-{2-[Bis-(2-hydroxy ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 2-methyl- phenylamino)- benzamide; N-{3-[4-(2-Hydroxy-ethyl)-piperazin-l-yl]-propyl}-2-(4-iodo-
2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyI- benzamide;
5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-l-yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-l-yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1 -yl- ethyl)-benzamide; 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N- { 2- [Bis-(2-hydroxy-ethyl)-amino] -ethyl } -5-fluoro-2-(4-iodo- 2-methyl- phenylamino)- benzamide;
5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1 -yl- propyl)-benzamide ;
N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl } -2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide ;
5-Chloro-N-(3-diethyIamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3 -piperidin- 1 -yl- propyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin- 1 -yl- ethyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1 -yl- ethyl)-benzamide;
N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-l-yl- propyl)-benzamide; [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy- pyrrolidin-1-yl)-;
5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-moφholin-4-yl- ethyl)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-l-yl- propyl)-benzamide;
[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin- 1 -; N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-
2-methyl-phenylamino)- benzamide;
N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;. 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide;
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide.; N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide;
5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide;
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;. 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide;
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide;
5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol ; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2r(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; or N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
8. The method of Claim 1 wherein the MEK inhibitor is a compound of Formula II
Figure imgf000096_0001
wherein:
R\a is hydrogen, hydroxy, Cj-Cg alkyl, Cj-Cg alkoxy, halo, trifluoromethyl, or CN;
R2a is hydrogen;
R3a, 4a, and R a independently are hydrogen, hydroxy, halo, trifluoromethyl, Cj-Cg alkyl, Cj-Cg alkoxy, nitro, CN, or
(O or NH)m-(CH2)n-R9a> where- R9a is hydrogen, hydroxy, CO2H or NRiOaRl la- n is 0-4; m is 0 or 1 ;
RjOa an(l R-l la independently are hydrogen or Cj-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-Cj-Cg alkyl; 0
II
Rga is hydrogen, Cj-Cg alkyl, C-Cj-Cg alkyl, aryl, aralkyl, or 3-C10 cycloalkyl; R7a is hydrogen, Cj-Cg alkyl, C2-C alkenyl, C2-Cg alkynyl, 3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NR9a); and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy; or Rga and R7a taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRj Oa^-l la' an°l me pharmaceutically acceptable salts, esters, amides or prodrugs thereof.
The method of Claim 1 wherein the MEK inhibitor is
4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3 -furylmethoxy)-benzamide ;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-( 1 -methylprop- 2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop- 2-ynyloxy)-benzamide ;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-
2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzarnide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop- 2-enyloxy)-benzamide; 3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(2-phenoxyethoxy)-benzamide ;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide;
3 ,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3 -ynyloxy)- benzamide;
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide ; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide ; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(n-propoxy)-benzamide;
5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyI- phenylamino)-benzamide
5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide; 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(3-methyl-pent-2-en-4-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3 -(3 -methoxy-phenyl)-prop-2-ynyloxy] -benzamide ;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2 -y lmethoxy)-benzamide ; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
(pyridin-3-ylmethoxy)-benzamide;
5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide;
5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide; 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide;
5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide;
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-yloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop- 2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3 ,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-
3-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(ethoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(cyclobutoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(isopropoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N- (2 -phenoxyethoxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(cyclopropyl- methoxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(n-propoxy)- benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N-(l-methyl- prop-2-ynyloxy)-benzamide ;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N- (3-(3-fluorophenyl)-prop-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N- (4,4-dimethylpent-2-ynyloxy)-benzamide;
3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino -N- (cyclopentoxy)-benzamide;
3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide;
5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide ;
5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide ;
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide;
3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
2--(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide;
4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide;
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide;
2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide;
5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide;
5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluoro-benzamide;
2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide;
N-Cyclopropylmethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide;
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; or 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- ,4-difluoro-benzamide.
PCT/US1997/023389 1997-02-28 1997-12-17 Method of treating or preventing septic shock by administering a mek inhibitor WO1998037881A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/355,680 US6251943B1 (en) 1997-02-28 1997-12-17 Method of treating or preventing septic shock by administering a MEK inhibitor
AU56103/98A AU5610398A (en) 1997-02-28 1997-12-17 Method of treating or preventing septic shock by administering a mek inhibitor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3927097P 1997-02-28 1997-02-28
US60/039,270 1997-02-28
US5615797P 1997-08-19 1997-08-19
US60/056,157 1997-08-19

Publications (1)

Publication Number Publication Date
WO1998037881A1 true WO1998037881A1 (en) 1998-09-03

Family

ID=26715966

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/023389 WO1998037881A1 (en) 1997-02-28 1997-12-17 Method of treating or preventing septic shock by administering a mek inhibitor

Country Status (3)

Country Link
US (1) US6251943B1 (en)
AU (1) AU5610398A (en)
WO (1) WO1998037881A1 (en)

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001426A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors
WO1999001421A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors
WO2000035435A1 (en) * 1998-12-15 2000-06-22 Warner-Lambert Company Use of a mek inhibitor for preventing transplant rejection
WO2000035436A2 (en) * 1998-12-16 2000-06-22 Warner-Lambert Company Treatment of arthritis with mek inhibitors
WO2000037141A1 (en) * 1998-12-22 2000-06-29 Warner-Lambert Company Combination chemotherapy
WO2000040235A2 (en) * 1999-01-07 2000-07-13 Warner-Lambert Company Treatment of asthma with mek inhibitors
WO2000041505A2 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Anthranilic acid derivatives
WO2000042002A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Sulphohydroxamic acids and sulphohydroxamates and their use as mek inhibitors
WO2000042003A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
WO2000042022A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzoheterocycles and their use as mek inhibitors
WO2000042029A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company 1-heterocycle substituted diarylamines
JP2000204079A (en) * 1999-01-13 2000-07-25 Warner Lambert Co Diarylamine
WO2001005390A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005392A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005393A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005391A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001068619A1 (en) * 2000-03-15 2001-09-20 Warner-Lambert Company 5-amide substituted diarylamines as mex inhibitors
DE10017480A1 (en) * 2000-04-07 2001-10-11 Transmit Technologietransfer Use of substances that act as MEK inhibitors for the manufacture of a medicament against DNA and RNA viruses
US6310060B1 (en) 1998-06-24 2001-10-30 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
WO2002018319A1 (en) * 2000-08-25 2002-03-07 Warner-Lambert Company Llc Process for making n-aryl-anthranilic acids and their derivatives
WO2002006213A3 (en) * 2000-07-19 2002-05-23 Warner Lambert Co Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
WO2002069960A2 (en) * 2001-03-06 2002-09-12 Axxima Pharmaceuticals Ag Use of mek inhibitors for treating inflammation and virus induced hemorrhagic shock
EP1255544A1 (en) * 2000-01-31 2002-11-13 Magainin Pharmaceuticals, Inc. Mucin synthesis inhibitors
EP1262176A1 (en) * 2001-05-09 2002-12-04 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
WO2003032988A1 (en) * 2001-10-17 2003-04-24 Sankyo Company, Limited Pharmaceutical composition
WO2003062191A1 (en) * 2002-01-23 2003-07-31 Warner-Lambert Company Llc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6686499B1 (en) 1999-04-21 2004-02-03 Warner-Lambert Company Method for making 2-(N-phenylamino)benzoic acids
US6703420B1 (en) 1999-03-19 2004-03-09 Bristol-Myers Squibb Pharma Company Amino-thio-acrylonitriles as MEK inhibitors
US6750241B2 (en) 1999-12-08 2004-06-15 Theravance, Inc. Protein kinase inhibitors
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6821963B2 (en) 1997-07-01 2004-11-23 Warner-Lambert Company 4-Bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US6846799B1 (en) 1998-08-18 2005-01-25 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
US7030119B1 (en) 1999-07-16 2006-04-18 Warner-Lambert Company Method for treating chronic pain using MEK inhibitors
US7060856B2 (en) 2003-10-21 2006-06-13 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US7160915B2 (en) 2003-07-24 2007-01-09 Warner-Lambert Company, Llc N-methyl-substituted benzamidazoles
WO2007132867A1 (en) 2006-05-15 2007-11-22 Takeda Pharmaceutical Company Limited Prophylactic and therapeutic agent for cancer
US7345051B2 (en) 2000-01-31 2008-03-18 Genaera Corporation Mucin synthesis inhibitors
US7354894B2 (en) 1998-08-18 2008-04-08 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7696218B2 (en) 2006-10-23 2010-04-13 Takeda San Diego, Inc. Substituted 1,3-dialkyl-2,4-dioxo-6-(arylamino)-1,2,3,4-tetrahydropyrimidine-5-hydroxamic acid inhibitors of MAPK/ERK kinase
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011070533A1 (en) 2009-12-10 2011-06-16 International Centre For Genetic Engineering And Biotechnology (Icgeb) Peptides and their derivatives inhibiting extracellular release of hiv-1 tat protein and hiv-1 replication
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8022057B2 (en) 2007-11-12 2011-09-20 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
JP2020189788A (en) * 2019-04-12 2020-11-26 国立大学法人 筑波大学 Sleep inducer heterocyclic compound
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1615357A (en) * 2001-11-21 2005-05-11 耶达研究及发展有限公司 Process for the manufacture of human mononuclear phagocytic leukocytes
WO2005046665A1 (en) * 2003-11-13 2005-05-26 Warner-Lambert Company Llc Combination chemotherapy comprising a mek inhibitor and a erbb1/2 receptor inhibitor
US20050171182A1 (en) * 2003-12-11 2005-08-04 Roger Briesewitz Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases
CA2561516A1 (en) * 2004-03-30 2005-10-13 Pfizer Products Inc. Combinations of signal transduction inhibitors
CA2684873A1 (en) * 2007-05-22 2009-02-19 Wisconsin Alumni Research Foundation Anti-bacterial drug targeting of genome maintenance interfaces
EP3204516B1 (en) 2014-10-06 2023-04-26 Dana-Farber Cancer Institute, Inc. Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response
MA41866A (en) 2015-03-31 2018-02-06 Massachusetts Gen Hospital SELF-ASSEMBLING MOLECULES FOR TARGETED DRUG DELIVERY

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022985A1 (en) * 1995-01-24 1996-08-01 Warner-Lambert Company 2-(2-amino-3-methoxyphenyl)-4-oxo-4h-[1]benzopyran for treating proliferative disorders
WO1996036642A1 (en) * 1995-05-19 1996-11-21 Davis Roger J Cytokine-, stress-, and oncoprotein-activated human protein kinase kinases
WO1997022704A1 (en) * 1995-12-20 1997-06-26 Signal Pharmaceuticals, Inc. Mitogen-activated protein kinase kinase mek6 and methods of use therefor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022985A1 (en) * 1995-01-24 1996-08-01 Warner-Lambert Company 2-(2-amino-3-methoxyphenyl)-4-oxo-4h-[1]benzopyran for treating proliferative disorders
WO1996036642A1 (en) * 1995-05-19 1996-11-21 Davis Roger J Cytokine-, stress-, and oncoprotein-activated human protein kinase kinases
WO1997022704A1 (en) * 1995-12-20 1997-06-26 Signal Pharmaceuticals, Inc. Mitogen-activated protein kinase kinase mek6 and methods of use therefor

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 103, no. 11, 16 September 1985, Columbus, Ohio, US; abstract no. 87588, A.N. GAIDUKEVICH ET AL.: "SYNTHESIS AND BIOLOGICAL ACTIVITY OF N-PHENYLANTHRANILIC ACID" XP002063638 *
CHEMICAL ABSTRACTS, vol. 109, no. 17, 24 October 1988, Columbus, Ohio, US; abstract no. 149000, T.I. SHUL'GA ET AL.: "SYNTHESIS AND PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES OF DIPHENYLAMINE-2-CARBOXYLIC ACID DERIVATIVES" XP002063639 *
CHEMICAL ABSTRACTS, vol. 77, no. 19, 6 November 1972, Columbus, Ohio, US; abstract no. 122522, I.S. SHUL'GA ET AL.: "SYNTHESIS OF 6-NITRODIPHENYLAMINE-2-CARBOXYLIC ACID DERIVATIVES THEIR PHYSICOCHEMICAL AND ANTIMICROBIAL PROPERTIES" XP002063640 *
D.T. DUDLEY ET AL.: "A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN KINASE CASCADE", PROC. NATL. ACAD. SCI., vol. 92, no. 17, 1995, pages 7686 - 7689, XP002063634 *
FARM. ZH., vol. 1, 1988, pages 42 - 45 *
FARM. ZH., vol. 27, no. 3, 1972, pages 84 - 85 *
H. BEKEMEIER ET AL.: "STRUCTURE-ACTIVITY RELATIONSHIP IN NONSTEROIDAL ANTIINFLAMMATORY AGENTS, INCLUDING QSAR IN FENAMATE DERIVATIVES", AGENTS ACTIONS SUPPL., 1982, pages 17 - 34, XP002063635 *
J.T. VAN DER BRUGGEN ET AL.: "MODULATION OF ENDOTOXIN-INDUCED TUMOR NECROSIS FACTOR alpha RELEASE BY HUMAN MONOCYTES", EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, vol. 27, no. S1, March 1997 (1997-03-01), pages A19, XP002063632 *
KHIM.-FARM. ZH., vol. 19, no. 3, 1985, pages 165 - 168 *
N.H. BERNER ET AL.: "SUBSTITUTED N-PHENYLANTHRANILIC ACID HYDRAZIDES AS POTENTIAL ANTIMALARIAL AND ANTIMICROBIAL AGENTS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 13, no. 3, 1970, pages 552 - 554, XP002063637 *
P. RAMANUJAM ET AL.: "ANTIFUNGAL ACTIVITY OF SOME N-SUBSTITUTED ANTHRANILIC ACID DERIVATIVES", PLANTA MEDICA, vol. 25, no. 1, 1974, pages 43 - 46, XP002063636 *
T.D. GEPPERT ET AL.: "LIPOPOLYSACCHARIDE SIGNALS ACTIVATION OF TUMOR NECROSIS FACTOR BIOSNTHESIS THROUGH THE RAS/RAF-1/MEK/MAPK PATHWAY", MOLECULAR MEDICINE, vol. 1, no. 1, 1994, pages 93 - 103, XP002063633 *

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7169816B2 (en) 1997-07-01 2007-01-30 Warner-Lambert Company 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US7019033B2 (en) 1997-07-01 2006-03-28 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
US6506798B1 (en) 1997-07-01 2003-01-14 Warner-Lambert Company 4-Arylamino, 4-aryloxy, and 4-arylthio diarylamines and derivatives thereof as selective MEK inhibitors
WO1999001426A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 4-bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as mek inhibitors
US6492363B2 (en) 1997-07-01 2002-12-10 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives
WO1999001421A1 (en) * 1997-07-01 1999-01-14 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as mek inhibitors
US6821963B2 (en) 1997-07-01 2004-11-23 Warner-Lambert Company 4-Bromo or 4-iodo phenylamino benzhydroxamic acid derivatives and their use as MEK inhibitors
US6310060B1 (en) 1998-06-24 2001-10-30 Warner-Lambert Company 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
US6846799B1 (en) 1998-08-18 2005-01-25 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7531500B2 (en) 1998-08-18 2009-05-12 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7354894B2 (en) 1998-08-18 2008-04-08 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
US7700547B2 (en) 1998-08-18 2010-04-20 The Regents Of The University Of California Preventing airway mucus production by administration of EGF-R antagonists
WO2000035435A1 (en) * 1998-12-15 2000-06-22 Warner-Lambert Company Use of a mek inhibitor for preventing transplant rejection
WO2000035436A3 (en) * 1998-12-16 2001-10-18 Warner Lambert Co Treatment of arthritis with mek inhibitors
WO2000035436A2 (en) * 1998-12-16 2000-06-22 Warner-Lambert Company Treatment of arthritis with mek inhibitors
WO2000037141A1 (en) * 1998-12-22 2000-06-29 Warner-Lambert Company Combination chemotherapy
WO2000040235A2 (en) * 1999-01-07 2000-07-13 Warner-Lambert Company Treatment of asthma with mek inhibitors
WO2000040235A3 (en) * 1999-01-07 2000-11-09 Warner Lambert Co Treatment of asthma with mek inhibitors
US6696440B1 (en) * 1999-01-07 2004-02-24 Warner-Lambert Company Treatment of asthma with MEK inhibitors
JP2000204079A (en) * 1999-01-13 2000-07-25 Warner Lambert Co Diarylamine
WO2000042022A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzoheterocycles and their use as mek inhibitors
US6750217B2 (en) 1999-01-13 2004-06-15 Warner-Lambert Company Benzenesulfonamide derivatives and their use as MEK inhibitors
WO2000041505A2 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Anthranilic acid derivatives
WO2000042002A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Sulphohydroxamic acids and sulphohydroxamates and their use as mek inhibitors
US6545030B1 (en) 1999-01-13 2003-04-08 Warner-Lambert Company 1-heterocycle substituted diarylamines
WO2000042003A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
WO2000042029A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company 1-heterocycle substituted diarylamines
US6469004B1 (en) 1999-01-13 2002-10-22 Warner-Lambert Company Benzoheterocycles and their uses as MEK inhibitors
JP2002534510A (en) * 1999-01-13 2002-10-15 ワーナー−ランバート・カンパニー Benzoheterocycles and their use as MEK inhibitors
WO2000041505A3 (en) * 1999-01-13 2000-10-19 Warner Lambert Co Anthranilic acid derivatives
US6440966B1 (en) 1999-01-13 2002-08-27 Warner-Lambert Company Benzenesulfonamide derivatives and their use as MEK inhibitors
US6455582B1 (en) * 1999-01-13 2002-09-24 Warner-Lambert Company Sulohydroxamic acids and sulohyroxamates and their use as MEK inhibitors
US6703420B1 (en) 1999-03-19 2004-03-09 Bristol-Myers Squibb Pharma Company Amino-thio-acrylonitriles as MEK inhibitors
US6686499B1 (en) 1999-04-21 2004-02-03 Warner-Lambert Company Method for making 2-(N-phenylamino)benzoic acids
WO2001005392A3 (en) * 1999-07-16 2001-07-19 Warner Lambert Co Method for treating chronic pain using mek inhibitors
US7030119B1 (en) 1999-07-16 2006-04-18 Warner-Lambert Company Method for treating chronic pain using MEK inhibitors
WO2001005390A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005392A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005393A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005391A2 (en) * 1999-07-16 2001-01-25 Warner-Lambert Company Method for treating chronic pain using mek inhibitors
WO2001005393A3 (en) * 1999-07-16 2001-05-10 Warner Lambert Co Method for treating chronic pain using mek inhibitors
WO2001005390A3 (en) * 1999-07-16 2001-05-17 Warner Lambert Co Method for treating chronic pain using mek inhibitors
WO2001005391A3 (en) * 1999-07-16 2001-07-19 Warner Lambert Co Method for treating chronic pain using mek inhibitors
US7037912B2 (en) 1999-12-08 2006-05-02 Theravance, Inc. Protein kinase inhibitors
US6750241B2 (en) 1999-12-08 2004-06-15 Theravance, Inc. Protein kinase inhibitors
US7173039B2 (en) 1999-12-08 2007-02-06 Theravance, Inc. Protein kinase inhibitors
US7345051B2 (en) 2000-01-31 2008-03-18 Genaera Corporation Mucin synthesis inhibitors
US7504409B2 (en) 2000-01-31 2009-03-17 Genaera Corporation Mucin synthesis inhibitors
EP1255544A4 (en) * 2000-01-31 2005-02-02 Genaera Corp Mucin synthesis inhibitors
EP1255544A1 (en) * 2000-01-31 2002-11-13 Magainin Pharmaceuticals, Inc. Mucin synthesis inhibitors
US7001905B2 (en) 2000-03-15 2006-02-21 Warner-Lambert Company Substituted diarylamines as MEK inhibitors
WO2001068619A1 (en) * 2000-03-15 2001-09-20 Warner-Lambert Company 5-amide substituted diarylamines as mex inhibitors
DE10017480A1 (en) * 2000-04-07 2001-10-11 Transmit Technologietransfer Use of substances that act as MEK inhibitors for the manufacture of a medicament against DNA and RNA viruses
JP2004505891A (en) * 2000-04-07 2004-02-26 メドルノバ　ゲゼルシャフト　フュア　メディシンシェ　イノバション　アウス　アカデミッシャー　フォルシュング　エムベーハー Application of substances acting as chain inhibitors on the Raf / MEK / ERK signaling chain in the production of drugs against DNA and RNA viruses
WO2001076570A2 (en) * 2000-04-07 2001-10-18 MedInnova Gesellschaft für medizinische Innovationen aus akademischer Forschung mbH Use of substances that act as cascade inhibitors of the raf/mek/erk signal cascade, for producing a medicament to treat dna and rna viruses
WO2001076570A3 (en) * 2000-04-07 2002-05-10 Transmit Technologietransfer Use of substances that act as cascade inhibitors of the raf/mek/erk signal cascade, for producing a medicament to treat dna and rna viruses
US7411001B2 (en) 2000-07-19 2008-08-12 Warner-Lambert Company Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
CZ303815B6 (en) * 2000-07-19 2013-05-15 Warner-Lambert Company Oxygenated ester of 4-iodophenylamino benzhydroxamic acid derivative and pharmaceutical composition containing thereof
AU2001273498B2 (en) * 2000-07-19 2006-08-24 Warner-Lambert Company Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
WO2002006213A3 (en) * 2000-07-19 2002-05-23 Warner Lambert Co Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids
US6960614B2 (en) 2000-07-19 2005-11-01 Warner-Lambert Company Oxygenated esters of 4-lodo phenylamino benzhydroxamic acids
WO2002018319A1 (en) * 2000-08-25 2002-03-07 Warner-Lambert Company Llc Process for making n-aryl-anthranilic acids and their derivatives
WO2002069960A2 (en) * 2001-03-06 2002-09-12 Axxima Pharmaceuticals Ag Use of mek inhibitors for treating inflammation and virus induced hemorrhagic shock
WO2002069960A3 (en) * 2001-03-06 2003-01-03 Axxima Pharmaceuticals Ag Use of mek inhibitors for treating inflammation and virus induced hemorrhagic shock
US6972298B2 (en) 2001-05-09 2005-12-06 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a MEK inhibitor
EP1262176A1 (en) * 2001-05-09 2002-12-04 Warner-Lambert Company Method of treating or inhibiting neutrophil chemotaxis by administering a mek inhibitor
WO2003032988A1 (en) * 2001-10-17 2003-04-24 Sankyo Company, Limited Pharmaceutical composition
WO2003062191A1 (en) * 2002-01-23 2003-07-31 Warner-Lambert Company Llc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US7078438B2 (en) 2002-01-23 2006-07-18 Warner-Lambert Company N-(4 substituted phenyl)-anthranilic acid hydroxamate esters
US6891066B2 (en) 2002-01-23 2005-05-10 Warner-Lambert Company N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US6770778B2 (en) 2002-01-23 2004-08-03 Pfizer Inc N-(4-substituted phenyl)-anthranilic acid hydroxamate esters
US7160915B2 (en) 2003-07-24 2007-01-09 Warner-Lambert Company, Llc N-methyl-substituted benzamidazoles
US7060856B2 (en) 2003-10-21 2006-06-13 Warner-Lambert Company Polymorphic form of N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide
US11597699B2 (en) 2005-10-07 2023-03-07 Exelixis, Inc. MEK inhibitors and methods of their use
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US7915250B2 (en) 2005-10-07 2011-03-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US8362002B2 (en) 2005-10-07 2013-01-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
WO2007132867A1 (en) 2006-05-15 2007-11-22 Takeda Pharmaceutical Company Limited Prophylactic and therapeutic agent for cancer
US7696218B2 (en) 2006-10-23 2010-04-13 Takeda San Diego, Inc. Substituted 1,3-dialkyl-2,4-dioxo-6-(arylamino)-1,2,3,4-tetrahydropyrimidine-5-hydroxamic acid inhibitors of MAPK/ERK kinase
US8088783B2 (en) 2006-10-23 2012-01-03 Qing Dong MAPK/ERK kinase inhibitors
US7943626B2 (en) 2006-10-23 2011-05-17 Takeda Pharmaceutical Company Limited Substituted 1,3-dialkyl-2,4-dioxo-6-(pyridylamino)-1,2,3,4-tetrahydropyrimidine-5-hydroxamic acid inhibitors of MAPK/ERK kinase
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8022057B2 (en) 2007-11-12 2011-09-20 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors
WO2010051933A2 (en) 2008-11-10 2010-05-14 Bayer Schering Pharma Aktiengesellschaft Substituted sulphonamido phenoxybenzamides
WO2011047795A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011047796A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted halophenoxybenzamide derivatives
WO2011047788A1 (en) 2009-10-21 2011-04-28 Bayer Schering Pharma Aktiengesellschaft Substituted benzosulphonamides
WO2011070533A1 (en) 2009-12-10 2011-06-16 International Centre For Genetic Engineering And Biotechnology (Icgeb) Peptides and their derivatives inhibiting extracellular release of hiv-1 tat protein and hiv-1 replication
WO2012055953A1 (en) 2010-10-29 2012-05-03 Bayer Pharma Aktiengesellschaft Substituted phenoxypyridines
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer
JP2020189788A (en) * 2019-04-12 2020-11-26 国立大学法人 筑波大学 Sleep inducer heterocyclic compound

Also Published As

Publication number Publication date
US6251943B1 (en) 2001-06-26
AU5610398A (en) 1998-09-18

Similar Documents

Publication Publication Date Title
WO1998037881A1 (en) Method of treating or preventing septic shock by administering a mek inhibitor
AU776788C (en) Treatment of arthritis with MEK inhibitors
AU756586C (en) 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
WO2000040235A2 (en) Treatment of asthma with mek inhibitors
EP1140291B1 (en) Combination chemotherapy comprising a mitotic inhibitor and a mek inhibitor
WO2000040237A1 (en) Antiviral method using mek inhibitors
US6310060B1 (en) 2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives and their use as MEK inhibitors
EP1140046A1 (en) Use of a mek inhibitor for preventing transplant rejection
US20040171632A1 (en) Combination chemotherapy
MXPA01005476A (en) Combination chemotherapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CZ EE GE HU ID IL IS JP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09355680

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998525997

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase